Synthesis of Fluorinated Amines: A Personal Account.

This Account highlights the recent contributions made by our laboratory in the development of novel strategies to synthesize fluorinated amines. These strategies allow the practitioner to efficiently access carbamoyl fluorides, thiocarbamoyl fluorides as well as trifluoromethylamines using CO2 or CS2 as benign C1 sources. In addition, a novel N(SCF3)CF3 moiety was synthesized. Noteworthy, we demonstrated that this reagent could also be used in radical- or electrophilic-based trifluoromethylthiolation reactions.

Validation of Selective Capture of Fimbriated Uropathogenic Escherichia coli by a Label-free Engineering Detection System Using Mannosylated Surfaces.

Label-free detection of pathogens is of major concern to the microbiologist community. Most procedures require several steps and amplification techniques. Carbohydrates are well-established receptors for host-pathogen interactions, which can be amplified using glycodendritic architectures on the basis of multivalent binding interactions. Given that uropathogenic Escherichia coli bacterial FimH is based on such mannopyranoside-binding interactions, we demonstrate herein that synthetic monomeric and trimeric thiolated α-d-mannosides can be effectively bound to gold substrate-functionalized self-assembled monolayers (SAMs) preactivated with maleimide functionalities. Mannosides grafted onto SAMs were followed using Quartz Crystal Microbalance with Dissipation (QCM-D). Binding recognition efficiency was first evaluated using the plant lectin from Canavalia ensiformis (ConA) also using QCM-D. We showed a direct correlation between the amount of mannoside bound and the lectin attachment. Even though there was less trimer bound (nM/cm2) to the surface, we observed a 7-fold higher amount of lectin anchoring, thus further demonstrating the value of the multivalent interactions. We next examined the relative fimbriated E. coli selective adhesion/capture to either the monomeric or the trimeric mannoside bound to the surface. Our results established the successful engineering of the surfaces to show E. coli adhesion via specific mannopyranoside binding but unexpectedly, the monomeric derivative was more efficient than the trimeric analog, which could be explained by steric hindrance. This approach strongly suggests that it could be broadly applicable to other Gram-negative bacteria sharing analogous carbohydrate-dependent binding interactions.

Synthesis & Evaluation of Novel Mannosylated Neoglycolipids for Liposomal Delivery System Applications.

Glycosylated NPs, including liposomes, are known to target various receptors involved in cellular carbohydrate transport, of which the mannoside binding receptors are attracting particular attention for their expression on various immune cells, cancers, and cells involved in maintaining central nervous system (CNS) integrity. As part of our interest in NP drug delivery, mannosylated glycoliposomal delivery systems formed from the self-assembly of amphiphilic neoglycolipids were developed, with a C12-alkyl mannopyranoside (ML-C12) being identified as a lead compoundcapable of entrapping, protecting, and improving the delivery of structurally diverse payloads. However, ML-C12 was not without limitations in both the synthesis of the glycolipids, and the physicochemical properties of the resulting glycoliposomes. Herein, the chemical syntheses of a novel series of mannosylated neoglycolipids are reported with the goal of further improving on the previous ML-C12 glyconanoparticles. The current work aimed to use a self-contingent strategy which overcomes previous synthetic limitations to produce neoglycolipids that have one exposed mannose residue, an aromatic scaffold, and two lipid tails with varied alkyl chains. The azido-ending carbohydrates and the carboxylic acid-ending lipid tails were ligated using a new one-pot modified Staudinger chemistry that differed advantageously to previous syntheses. The formation of stable neoglycoliposomes of controllable and ideal sizes (≈100-400 nm) was confirmed via dynamic light scattering (DLS) experiments and transmission electron microscopy (TEM). Beyond chemical advantages, the present study further aimed to establish potential improvements in the biological activity of the neoglycoliposomes. Concanavalin A (Con A) agglutination studies demonstrated efficient and stable cross-linking abilities dependent on the length of the linkers and lipid tails. The efficacy of the glycoliposomes in improving cytosolic uptake was investigated using Nile Red as probe in immune and cancer cell lines. Preliminary ex vivo safety assessments showed that the mannosylated glycoliposomes are hemocompatible, and non-immunogenic. Finally, using a model peptide therapeutic, the relative entrapment capacity and plasma stability of the optimal glycoliposome delivery system was evaluated and compared to the previous neoglycoliposomes. Overall, the new lead glycoliposome showed improved biological activity over ML-C12, in addition to having several chemical benefits including the lack of stereocenters, a longer linker allowing better sugar availability, and ease of synthesis using novel one-pot modified Staudinger chemistry.

Metal-Free SF6 Activation: A New SF5 -Based Reagent Enables Deoxyfluorination and Pentafluorosulfanylation Reactions.

The activation of SF6 , a potent greenhouse gas, under metal-free and visible light conditions is reported. Herein, mechanistic investigations including EPR spectroscopy, NMR studies and cyclic voltammetry allowed the rational design of a new fluorinating reagent which was synthesized from the 2-electron activation of SF6 with commercially available TDAE. This new SF5 -based reagent was efficiently employed for the deoxyfluorination of CO2 and the fluorinative desulfurization of CS2 allowing the formation of useful fluorinated amines. Moreover, for the first time we demonstrated that our SF5 -based reagent could afford the mild generation of Cl-SF5 gas. This finding was exploited for the chloro-pentafluorosulfanylation of alkynes and alkenes.

Metal-free nucleophilic trifluoromethylselenolation via an iodide-mediated umpolung reactivity of trifluoromethylselenotoluenesulfonate.

We report herein a practical method to generate CF3Se- (and RFSe-) anions from shelf-stable reagents under iodide activation. Metal-free nucleophilic trifluoromethylselenolations have been then performed with this in situ-generated anion. Perfluoroalkylselenolations have also been described.